The inhibitory activity associated with myelin is a major obstacle for successful axon regeneration in the adult mammalian central nervous system (CNS)1,2. In addition to myelin associated glycoprotein (MAG)3-4 and Nogo-A5-7, evidence suggests the existence of other inhibitors in CNS myelin8. We show that a glycosylphosphatidylinositol (GPI)-anchored CNS myelin protein, oligodendrocyte-myelin glycoprotein (OMgp), is a potent inhibitor of neurite outgrowth. Like Nogo-A, OMgp contributes significantly to the inhibitory activity associated with CNS myelin. To elucidate the mechanisms that mediate this inhibitory activity of OMgp, we screened an expression library and identified the Nogo receptor (NgR)9 as a high affinity OMgp binding protein. Cleavage of NgR and other GPI-linked proteins from the cell surface renders dorsal root ganglion axons insensitive to OMgp. Introduction of exogenous NgR confers OMgp-responsiveness to otherwise insensitive neurons. We conclude that OMgp is an physiological neurite outgrowth inhibitor that acts through and is a physiological ligand of the NgR and its associated receptor complex. We show that Interfering with the OMgp/NgR pathway allows lesioned axons to regenerate after injury in vivo.